Seneca Valley Virus sounds like the last bug you’d want to catch, but it could be the next breakthrough cancer therapy.
Now, scientists at the Okinawa Institute of Science and Technology (OIST) and the University of Otago have described exactly how the virus interacts with tumors — and why it leaves healthy tissues alone.
The study, published in the Proceedings of the National Academy of Sciences of the United States of America on October 29, 2018, provides the first detailed images of the complex Seneca Valley Virus forms with its preferred receptor. The researchers used cryo-electron microscopy to capture images of over 7000 particles and render the structure in high-resolution. They predict their results will help scientists develop the virus, and other viral drug candidates, for clinical use.
“If you have a virus that targets cancer cells and nothing else, that’s the ultimate cancer fighting tool,” said Prof. Matthias Wolf, principal investigator of the Molecular Cryo-Electron Microscopy Unit at OIST and co-senior author of the study. “I expect this study will lead to efforts to design viruses for cancer therapy.”
An international team of researchers at OIST and University of Otago have used the Nobel-winning cryo-electron microscopy method to reconstruct the structure of Seneca Valley virus, abbreviated SVV, at near-atomic resolution.
The structure shows how the virus binds to its cellular receptor, the Anthrax toxin receptor. Type 1 of this receptor is selectively expressed in up to 60% of human cancer cells and allows the virus to infect and destroy them while not affecting healthy cells. The study, which was published in the journal Proceedings of the National Academy of Sciences USA, reveals how the virus can recognize its target and leave normal tissue alone.
Provided by Matthias Wolf, additional edits by Andrew Scott
Targeting two-thirds of human cancers
In the past few years, so-called “virotherapy” has grown up as a new branch of cancer immunotherapy. Anticancer viruses tend to target tumors while sparing the healthy cells around them, and many already exist in nature. Scientists hunt down these cancer-killers, study their attack strategies, and optimize their effectiveness through genetic modification. The U.S. Food and Drug Administration has already approved one viral therapy to treat Stage IV melanoma, and other viral drug candidates appear promising in clinical trials.
Seneca Valley Virus stands out as a potential virotherapy for one key reason: it selectively targets a receptor found coating tumor cells in over 60 percent of human cancers. The receptor, known as ANTXR1, is only expressed on tumors, but it has a cousin that only appears on healthy tissues, called ANTXR2. Seneca Valley Virus doesn’t bind with the similar receptor on healthy cells — it only shows strong affinity for ANTXR1. The study’s authors wanted to know why.
“The differences between the two receptors are subtle, but nonetheless, these subtle differences make one bind the virus with high affinity while the other doesn’t,” said Wolf. The researchers found that the outer shell of the Seneca Valley Virus locks tightly onto specific structural features of ANTXR1 — features that aren’t conserved in ANTXR2. “The components must fit together like a key in a lock — this is a highly evolved system where everything fits perfectly.”
Designing an optimal cancer therapy
Seneca Valley Virus has already demonstrated its cancer-fighting abilities in Phase I clinical trials in pediatric solid tumors and Phase II trials in small-cell lung cancers. But there’s one problem: the body builds up immunity to the virus within three weeks and squashes the bug before its work is done.
“If you give a virus as a vaccine, you want an immune response — there, the goal is the destruction of the virus,” said Wolf. “In this case, you want the opposite. You want the virus to evade the immune system, continue to replicate and kill the cancer cells.”
“By looking at this structure, we can learn what part of the virus is essential for binding to the receptor and which is not,” said Prof. Mihnea Bostina, the academic director of the Otago Centre for Electron Microscopy at the University of Otago and co-senior author of the study. “If we want to make the virus ‘better,’ we can try to change the non-essential parts in order to escape the action of the immune system while leaving the essential part intact.”
With deeper understanding of how the virus works, scientists may be able to outsmart the body’s immune system and protect their mighty cancer-killer. In principle, Seneca Valley Virus could also be modified to recognize different receptors, Wolf said, rendering it a broadly applicable weapon in the fight against cancer.
“I have always been intrigued by ways how we can make use of naturally occurring microorganisms for our benefit,” said Nadishka Jayawardena, a graduate student at the University of Otago and first author of the study. “Being able to work on a virus that can kill cancers is very rewarding, especially knowing that one day our findings could potentially lead to tackling a major global health issue.”
The Latest on: Seneca Valley Virus
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The Latest on: Seneca Valley Virus
- Structural basis for anthrax toxin receptor 1 recognition by Seneca Valley Viruson November 12, 2018 at 4:00 pm
Anthrax toxin receptor 1 (ANTXR1), also known as Tumor Endothelial Marker 8, is overexpressed on the surface of tumor cells in over 60% of human cancers. A serious drawback for developing specific ...
- Review of Seneca Valley Virus: A Call for Increased Surveillance and Researchon May 10, 2018 at 5:00 pm
State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research ...
- Seneca Valley Virus growing problem in U.S.on December 17, 2017 at 4:00 pm
Seneca Valley Virus, an illness in pigs, is on the rise in parts of the United States, and that should put Canadian hog producers on alert. Dr. Julia Keenliside, veterinary epidemiologist with Alberta ...
- NCI Drug Dictionaryon November 29, 2017 at 3:33 pm
The NCI Drug Dictionary contains technical definitions and synonyms for drugs/agents used to treat patients with cancer or conditions related to cancer. Each drug entry includes links to check for ...
- Seneca Valley Virus-001 After Chemotherapy in Treating Patients With Extensive-Stage Small Cell Lung Canceron May 7, 2017 at 5:00 pm
RATIONALE: A virus called Seneca Valley virus-001 (NTX-010) may be able to kill tumor cells without damaging normal cells. It is not yet known whether NTX-010 is more effective than a placebo in ...
- Seneca Valley pig virus in central Wisconsinon January 31, 2017 at 4:00 pm
ATHENS, Wis. (WSAW) --Seneca Valley Virus is showing up in pigs in Wisconsin slaughterhouses, with many of the 159 reported cases found in Clark County. Despite the virus being in Wisconsin, it is not ...
- Structure of Seneca Valley Virus-001, An oncolytic picornavirus representing a new genuson October 7, 2016 at 7:27 am
The crystal structure of Seneca Valley Virus-001, SVV-001, the representative member of a new genus “Senecavirus” is reported at 2.3Å resolution. SVV-001 is the first naturally occurring ...
- Oncolytic Seneca Valley Virus: past perspectives and future directionson February 3, 2016 at 4:00 pm
Figure 1 Properties of SVV-001 as an oncolytic virus. Notes: The cartoon demonstrates SVV-001 being administered into a patient with a neuroendocrine tumor as an IV infusion. SVV-001 displays tropism ...
- Seneca Valley Virus In Swineon October 20, 2015 at 6:23 am
Pork producers might be aware of a disease circulating in pigs call the Seneca Valley Virus (SVV). As the daily observations and health status checks of your herd are completed, producers should be ...
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